Abstract
A five-generation kindred (19 affected, two obligate carriers and 20 unaffected) from Oklahoma USA, in which familial benign (hypocalciuric) hypercalcaemia (FBH) was associated with a developmental elevation in serum parathyroid hormone (PTH) levels, has been investigated for linkage to the candidate chromosomal regions 3q21-q24 and 19p13.3, 11q13, and 11p15, to which the genes for FBH, multiple endocrine neoplasia type 1 (MEN1) and PTH have been mapped respectively. By means of 17 polymorphic markers from these regions, linkage was excluded [LOD scores <-2.00 at (θ) = 0.05−0.25]. In addition, an analysis of multipoint crossovers and use of the LINKMAP program confirmed the exclusion from these regions. Thus, this form of FBH, designated the Oklahoma variant FBH(Ok), is not linked to markers that segregate with FBH, MEN1 and PTH; our results indicate further genetic heterogeneity and the presence of a third locus for FBH.
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Brown EM, Gamba G, Riccardi D, Lombardi M, Butters R, Kifor O, Sun A, et al (1993) Cloning expression, and characterisation of an extracellular Ca2+sensing receptor from bovine parathyroid. Nature 366:575–580
Chou Y-HW, Brown EM, Levi T, Crowe G, Atkinson AB, Arnqvist HJ, Toss G, et al (1992) The gene responsible for familial hypocalciuric hypercalcemia maps to chromosome 3q in four unrelated families. Nature Genet 1:295–300
Donis-Keller HP, Green C, Helms S, Cartenhour B, Weiffenbach K, Stevens TP, Keith DW, et al (1987) A genetic map of the human genome. Cell 51:319–337
Eubanks JH, Selleri L, Hart R, Rosette C, Evans GA (1991) Isolation, localisation and physical mapping of a highly polymorphic locus on human chromosome 11q13. Genomics 11:720–729
Farrar GJ, McWilliam P, Bradley DG, Kenna Lawler PM, Shar EM, Humphries MM, et al (1990) Autosomal dominant retinitis pigmentosa: linkage to rhodopsin and evidence for genetic heterogeneity. Genomics 8:35–40
Heath H III, Jackson CE, Otterud B, Leppert MF (1993) Genetic linkage analysis in familial benign (hypocalciuric) hypercalcemia: evidence for locus heterogeneity. Am J Hum Genet 53: 193–200
Heath H III, Odelberg S, Brown D, Hill VM, Robertson M, Jackson CE, Teh BT, Hayward N, et al (1994) Sequence analysis of the parathyroid cell calcium receptor (CaR) gene in familial benign hypercalcemia (FBH): a multplicity of mutations? J Bone Miner Res 9 (Suppl 1):C426
Hudson TJ, Engelstein M, Lee MK, Ho EC, Rubenfield MJ, Adams CP, Housman DE, et al (1992) Isolation and chromosomal assignment of 100 highly informative human simple sequence repeat polymorphisms. Genomics 13:622–629
Iwasaki HP, Stewart W, Dilley WG, Holt MS, Steinbrueck TD, Wells SA Jr, Donis-Keller HP (1992) A minisatellite and a microsatellite polymorphism within 1. 5 kb at the human muscle glycogen phosphorylase (PYGM) locus can be amplified by PCR and have combined informativeness of PIC 0. 95. Genomics 13:7–15
Lamoneh A-M, Barankiewicz TJ, Huntingdon FW, Mahuran DJ, Quan F, Gravel RA (1986) Isolation of cDNA clones coding for the a and b chains of human proprionyl-CoA carboxylase: chromosomal assignments and DNA polymorphisms associated with PCCA and PCCB genes. Proc Natl Acad Sci USA 83:4864–4868
Larsson C, Skogseid B, Oberg K, Nakamura Y, Nordenskjold M (1988) Multiple endocrine neoplasia type 1 gene maps to chromosome 11 and is lost in insulinoma. Nature 332:85–87
Law W, Heath H III (1985) Familial benign hypercalcemia (hypocalciuric hypercalcemia). Clinical and pathogenetic studies in 21 families. Ann Intern Med 102:511–519
Lev AA, Rosen DR, Kos C, Clifford E, Landes G, Hauser SL, Brown RH Jr (1993) Human ciliary neurotropic factor: localisation to the proximal region of the long arm of chromosome 11 and association with CA/GT dinucleotide repeat. Genomics 16:539–541
Marx SJ, Attie MF, Levine MA, Spiegel AM, Downs RW Jr, Lasker RD (1981) The hypocalciuric or benign variant of familial hypercalcemia: clinical and biochemical features in 15 kindreds. Medicine (Baltimore) 60:397–412
Marx SJ, Attie MF, Spiegel AM, Levine MA, Lasker RD, Fox M (1982) An association between neonatal severe primary hyperparathyroidism and familial hypocalciuric hypercalcemia in three kindreds. N Engl J Med 306:257–264
McKusick VA (1990) Mendelian inheritance in man, 9th edn. Johns Hopkins University Press, Baltimore, 501–502
McMurtry CT, Schranck FW, Walkenhorst DA, Murphy WA, Kocher DB, Teitelbaum SL, Rupich RC, Whyte MP (1992) Significant developmental elevation in serum parathyroid hormone levels in a large kindred with familial benign (hypocalciuric) hypercalcemia. Am J Med 93:247–258
Menko FH, Bijvoet OLM, Fronen JLHH, Sandler LM, Adami S, O'Riordan JLH, Schopman W, et al (1983) Familial benign hypercalcaemia, study of a large family. Q J Med 206:120–140
Moffatt MF (1993) Dinucleotide repeat polymorphisms at the D11S480 locus. Hum Mol Genet 2:492
Mountjoy KG, Robbins LS, Mortrud MT, Cone RD (1992) The cloning of a family of genes that encode the melanocortin receptors. Science 257:1248–1251
Nakamura Y, Cowen J, Krapcho K, O'Connell P, Leppert M, Lathrop GM, Lalouel J-M (1989) Isolation and mapping of a polymorphic DNA sequence pJCZ3.1 on chromosome 19 (D19S20). Nucleic Acids Res 16:1229
Naylor SL, Sakaguchi AY, Szoka P, Hendy GN, Kronenberg HM, Rich A, Shows TB (1983) Human parathyroid hormone gene (PTH) is on the short arm of chromosome 11. Somat Cell Genet 9:609–616
NIH/CEPH Collaborative Mapping Group (1992) A comprehensive genetic linkage map of the human genome. Science 258:67–86
Pang JT, Wooding C, Leigh SEA, Taggart RT, Sheffield V, Jones C, Thakker RV (1993) Molecular genetic mapping of 13 markers from chromosome 11q13 in 33 families with multiple endocrine neoplasia type 1. J Bone Miner Res 8: S77
Parkinson DB, Shaw NJ, Himsworth RL, Thakker RV (1993) Parathyroid hormone gene analysis in autosomal hypoparathyroidism using an intragenic tetranucleotide (AAAT) n polymorphism. Hum Genet 91:281–284
Pearce SHS, Trump D, Wooding C, Besser GM, Chew SL, Heath DA, Hughes IA, Thakker RV (1994) Four novel mutations in the calcium-sensing receptor gene associated with familial enign (hypocalciuric) hypercalcaemia. J Bone Miner Res 9 (Suppl 1):99
Pollak MR, Brown EM, Chou Y-HW, Hebert SC, Marx SJ, Steinmann B, Levi T, et al (1993) Mutations in the human Ca2+sensing receptor gene cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Cell 75:1297–1303
Pollak MR, Chou Y-HW, Marx SJ, Steinman B, Cole DEC, Brandi ML, Papapoulos SE, et al (1994) Familial hypocalciuric hypercalcemia and neonatal severe hyperparatyroidism effects of mutant gene dose on phenotype. J Clin Invest 93:1108–1112
Polymeropoulos MH, Xiao H, Rath DS, Merril CR (1990) Dinucleotide repeat polymorphism at the int-2 proto-oncogene locus (INT2). Nucleic Acids Res 18:7468
Polymeropoulos MH, Xiao H, Rath DS, Merril CR (1991) Tetranucleotide repeat polymorphism at the prostatic acid phosphatase (ACPP) gene. Nucleic Acids Res 19:4792
Scheinman SJ, Pook MA, Wooding C, Pang JT, Frymoyer PA, Thakker RV (1993) Mapping the gene causing X-linked recessive nephrolithiasis to Xp11. 22 by linkage analysis studies. J Clin Invest 91:2351–2357
Schmidtke J, Pape B, Krengel U, Langenbeck U, Cooper D, Breyel EA, Mayer H (1984) Restriction fragment length polymorphisims at the human parathyroid hormone gene locus. Hum Genet 67:428–431
Thakker RV, Bouloux P, Wooding C, Chotai K, Broad PM, Spurr NK, Besser GM, et al (1989) Association of parathyroid tumours in multiple endocrine neoplasia type 1 with loss of alleles on chromosome 11. N Engl J Med 321:218–224
Thakker RV, Davies KE, Whyte MP, Wooding C, O'Riordan JLH (1990) Mapping the gene causing X-linked recessive idiopathic hypoparathyroidism to Xq26-Xq27 by linkage studies. J Clin Invest 86:40–45
Thakker RV, Wooding C, Pang JT, Farren B, Harding B, Anderson DC, Besser GM (1993) Linkage analysis of 7 polymorphic markers at chromosome 11q11. 2–11q13 in 27 multiple endocrine neoplasia type 1 families. Ann Hum Genet 57:17–25
Weber JL, May PE, Patterson D, Drabkin H, Killary AM (1990) Dinucleotide repeat polymorphism at the D3S196 locus. Nucleic Acids Res 18:4635
Weissenbach J, Gyapay G, Dib C, Vignal A, Morissette J, Millasseau P, Vaysseix G, Lathrop M (1992) A second generation linkage map of the human genome. Nature 359:794–801
Williamson R, Bowcock A, Kidd K, Pearson P, Schmidtke J, Ceverha P, Chipperfield M, et al (1991) Report of the DNA committee and catalogues of cloned and mapped genes, markers formatted for PCR and DNA polymorphisms. Cytogenet Cell Genet 58:1190–1832
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Trump, D., Whyte, M.P., Wooding, C. et al. Linkage studies in a kindred from Oklahoma, with familial benign (hypocalciuric) hypercalcaemia (FBH) and developmental elevations in serum parathyroid hormone levels, indicate a third locus for FBH. Hum Genet 96, 183–187 (1995). https://doi.org/10.1007/BF00207376
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DOI: https://doi.org/10.1007/BF00207376